Medicine and Health Sciences Commons^™

Hormonal Therapies Up-Regulate Manf And Overcome Female Susceptibility To Immune Checkpoint Inhibitor Myocarditis, Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A Huang, Tina K Nguyen, Sergey D Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A Calin, Jie Cheng, Bora Lim, Lorenz H Lehmann, Joe-Elie Salem, Douglas B Johnson, Michael A Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J Moslehi, Chunru Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis …

Broad-Acting Therapeutic Effects Of Mir-29b-Chitosan On Hypertension And Diabetic Complications, David M Jensen, Peng Han, Lingegowda S Mangala, Gabriel Lopez-Berestein, Anil K Sood, Jing Liu, Alison J Kriegel, Kristie Usa, Michael E Widlansky, Mingyu Liang

Faculty, Staff and Student Publications

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced …

Bile Acids Regulate The Epithelial Na+ Channel In Native Tissues Through Direct Binding At Multiple Sites, Xue-Ping Wang, Viktor Tomilin, Andrew J Nickerson, Runze Tian, Merve Ertem, Abagail Mckernan, Xiaoguang Lei, Oleh Pochynyuk, Ossama B Kashlan

Faculty, Staff and Student Publications

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that …

Oxytocin Signaling Is Necessary For Synaptic Maturation Of Adult-Born Neurons, Brandon T Pekarek, Mikhail Kochukov, Brittney Lozzi, Timothy Wu, Patrick J Hunt, Burak Tepe, Elizabeth Hanson Moss, Evelyne K Tantry, Jessica L Swanson, Sean W Dooling, Mayuri Patel, Benjamin D W Belfort, Juan M Romero, Suyang Bao, Matthew C Hill, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial …

Mucins Muc5ac And Muc5b Are Variably Packaged In The Same And In Separate Secretory Granules, Oanh N Hoang, Anna Ermund, Ana M Jaramillo, Dalia Fakih, Cory B French, Jose R Flores, Harry Karmouty-Quintana, Jesper M Magnusson, Giorgio Fois, Michael Fauler, Manfred Frick, Peter Braubach, Joshua B Hales, Richard C Kurten, Reynold Panettieri, Leoncio Vergara, Camille Ehre, Roberto Adachi, Michael J Tuvim, Gunnar C Hansson, Burton F Dickey

Faculty, Staff and Student Publications

No abstract provided.

Is Loss Of P53 A Driver Of Ductal Carcinoma In Situ Progression?, Rhiannon L Morrissey, Alastair M Thompson, Guillermina Lozano

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive carcinoma. Multiple studies have shown that DCIS lesions typically possess a driver mutation associated with cancer development. Mutation in the TP53 tumour suppressor gene is present in 15-30% of pure DCIS lesions and in ~30% of invasive breast cancers. Mutations in TP53 are significantly associated with high-grade DCIS, the most likely form of DCIS to progress to invasive carcinoma. In this review, we summarise published evidence on the prevalence of mutant TP53 in DCIS (including all DCIS subtypes), discuss the availability of mouse models for the study of DCIS …

Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis And Muscle Wasting Through Metabolic Reprogramming In Pancreatic Cancer, Zhijun Zhou, Yu Ren, Jingxuan Yang, Mingyang Liu, Xiuhui Shi, Wenyi Luo, Kar-Ming Fung, Chao Xu, Michael S Bronze, Yuqing Zhang, Courtney W Houchen, Min Li

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.

METHODS: Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein …

Nab-Paclitaxel, Capecitabine, And Radiation Therapy After Induction Chemotherapy In Treating Patients With Locally Advanced And Borderline Resectable Pancreatic Cancer: Phase 1 Trial And Imaging-Based Biomarker Validation, Eugene J Koay, Mohamed Zaid, Maureen Aliru, Polycarpe Bagereka, Arie Van Wieren, Maria Jovie Rodriguez, Galia Jacobson, Robert A Wolff, Michael Overman, Gauri Varadhachary, Shubham Pant, Huamin Wang, Ching-Wei Tzeng, Naruhiko Ikoma, Michael Kim, Jeffrey E Lee, Matthew Hg Katz, Eric Tamm, Priya Bhosale, Cullen M Taniguchi, Emma B Holliday, Grace L Smith, Ethan B Ludmir, Bruce D Minsky, Christopher H Crane, Albert C Koong, Prajnan Das, Xuemei Wang, Milind Javle, Sunil Krishnan

Faculty, Staff and Student Publications

PURPOSE: Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

METHODS AND MATERIALS: Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m

RESULTS: Twenty-three patients started and finished …

Inhibition Of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance To Programmed Cell Death 1 Blockade In Malignant Mesothelioma, Hee-Jin Jang, Cynthia Y Truong, Eric M Lo, Hudson M Holmes, Daniela Ramos, Maheshwari Ramineni, Ju-Seog Lee, Daniel Y Wang, Massimo Pietropaolo, R Taylor Ripley, Bryan M Burt, Hyun-Sung Lee

Faculty, Staff and Student Publications

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.

METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested …

Investigation Of Murine Host Sex As A Biological Variable In Epithelial Barrier Function And Muscle Contractility In Human Intestinal Organoids, Brooke T Beanland, Eoin P Mcneill, David J Sequeira, Hasen Xue, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

Intestinal failure (IF) occurs when intestinal surface area or function is not sufficient to support digestion and nutrient absorption. Human intestinal organoid (HIO)-derived tissue-engineered intestine is a potential cure for IF. Research to date has demonstrated successful HIO transplantation (tHIO) into mice with significant in vivo maturation. An area lacking in the literature is exploration of murine host sex as a biological variable (SABV) in tHIO function. In this study, we investigate murine host SABV in tHIO epithelial barrier function and muscle contractility. HIOs were generated in vitro and transplanted into nonobese diabetic, severe combined immunodeficiency gamma chain deficient male …

Differential Integrated Stress Response And Asparagine Production Drive Symbiosis And Therapy Resistance Of Pancreatic Adenocarcinoma Cells, Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy Mccarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca Di Magliano, Claus Jorgensen, Costas A Lyssiotis

Faculty, Staff and Student Publications

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive …

T Cells Specific For Α-Myosin Drive Immunotherapy-Related Myocarditis, Margaret L Axelrod, Wouter C Meijers, Elles M Screever, Juan Qin, Mary Grace Carroll, Xiaopeng Sun, Elie Tannous, Yueli Zhang, Ayaka Sugiura, Brandie C Taylor, Ann Hanna, Shaoyi Zhang, Kaushik Amancherla, Warren Tai, Jordan J Wright, Spencer C Wei, Susan R Opalenik, Abigail L Toren, Jeffrey C Rathmell, P Brent Ferrell, Elizabeth J Phillips, Simon Mallal, Douglas B Johnson, James P Allison, Javid J Moslehi, Justin M Balko

Faculty, Staff and Student Publications

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, …

Transgenic Force Sensors And Software To Measure Force Transmission Across The Mammalian Nuclear Envelope In Vivo, Kelli D Fenelon, Evan Thomas, Mohammad Samani, Min Zhu, Hirotaka Tao, Yu Sun, Helen Mcneill, Sevan Hopyan

2020-Current year OA Pubs

Nuclear mechanotransduction is a growing field with exciting implications for the regulation of gene expression and cellular function. Mechanical signals may be transduced to the nuclear interior biochemically or physically through connections between the cell surface and chromatin. To define mechanical stresses upon the nucleus in physiological settings, we generated transgenic mouse strains that harbour FRET-based tension sensors or control constructs in the outer and inner aspects of the nuclear envelope. We knocked-in a published esprin-2G sensor to measure tensions across the LINC complex and generated a new sensor that links the inner nuclear membrane to chromatin. To mitigate challenges …

Aging-Associated Regγ Proteasome Decline Predisposes To Tauopathy, Jialu Tu, Haiyang Zhang, Ting Yang, Yun Liu, Solomon Kibreab, Yunpeng Zhang, Liangcai Gao, Robb E Moses, Bert W O'Malley, Jianru Xiao, Xiaotao Li

Faculty, Staff and Students Publications

The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found …

Combination Of Aibp, Apoa-I, And Aflibercept Overcomes Anti-Vegf Resistance In Neovascular Amd By Inhibiting Arteriolar Choroidal Neovascularization, Zhao Zhang, Megan M Shen, Yingbin Fu

Faculty, Staff and Students Publications

PURPOSE: Anti-VEGF resistance represents a major unmet clinical need in the management of choroidal neovascularization (CNV). We have previously reported that a combination of AIBP, apoA-I, and an anti-VEGF antibody overcomes anti-VEGF resistance in laser-induced CNV in old mice in prevention experiments. The purpose of this work is to conduct a more clinically relevant study to assess the efficacy of the combination of AIBP, apoA-I, and aflibercept in the treatment of anti-VEGF resistance of experimental CNV at different time points after laser photocoagulation.

METHODS: To understand the pathobiology of anti-VEGF resistance, we performed comprehensive examinations of the vascular morphology of …

Stat6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis And Asthma, A Model Of Unified Airway Disease, Meng Lin, Amy T Ku, Jie Dong, Fei Yue, Weiyu Jiang, Ahmed Atef Ibrahim, Fanglue Peng, Chad J Creighton, Chandandeep Nagi, Carolina Gutierrez, Jeffrey M Rosen, Xiang H-F Zhang, Susan G Hilsenbeck, Xi Chen, Yi-Chieh Nancy Du, Shixia Huang, Aiping Shi, Zhimin Fan, Yi Li

Faculty, Staff and Student Publications

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in …

A Microtubule-Connexin-43 Regulatory Link Suppresses Arrhythmias And Cardiac Fibrosis In Duchenne Muscular Dystrophy Mice, Eric Himelman, Julie Nouet, Mauricio A Lillo, Alexander Chong, Delong Zhou, Xander H T Wehrens, George G Rodney, Lai-Hua Xie, Natalia Shirokova, Jorge E Contreras, Diego Fraidenraich

Faculty, Staff and Students Publications

Dilated cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), an inherited degenerative disease of the cardiac and skeletal muscle caused by absence of the protein dystrophin. We showed one hallmark of DMD cardiomyopathy is the dysregulation of cardiac gap junction channel protein connexin-43 (Cx43). Proper Cx43 localization and function at the cardiac intercalated disc (ID) is regulated by post-translational phosphorylation of Cx43-carboxy-terminus residues S325/S328/S330 (pS-Cx43). Concurrently, Cx43 traffics along microtubules (MTs) for targeted delivery to the ID. In DMD hearts, absence of dystrophin results in a hyperdensified and disorganized MT cytoskeleton, yet the link with pS-Cx43 …

Inositol Phosphorylceramide Synthase Null Leishmania Are Viable And Virulent In Animal Infections Where Salvage Of Host Sphingomyelin Predominates, F Matthew Kuhlmann, Phillip N Key, Suzanne M Hickerson, John Turk, Fong-Fu Hsu, Stephen M Beverley

2020-Current year OA Pubs

Many pathogens synthesize inositol phosphorylceramide (IPC) as the major sphingolipid (SL), differing from the mammalian host where sphingomyelin (SM) or more complex SLs predominate. The divergence between IPC synthase and mammalian SL synthases has prompted interest as a potential drug target. However, in the trypanosomatid protozoan Leishmania, cultured insect stage promastigotes lack de novo SL synthesis (Δspt2

A New Mouse Model Of Charcot-Marie-Tooth 2j Neuropathy Replicates Human Axonopathy And Suggest Alteration In Axo-Glia Communication, Ghjuvan'ghjacumu Shackleford, Yo Sasaki, Et Al.

2020-Current year OA Pubs

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 …

Histone-Stimulated Platelet Adhesion To Mouse Cremaster Venules In Vivo Is Dependent On Von Willebrand Factor, Justin A Courson, Fong W Lam, Kimberly W Langlois, Rolando E Rumbaut

Faculty, Staff and Students Publications

Objective: Extracellular histones are known mediators of platelet activation, inflammation, and thrombosis. Von Willebrand Factor (vWF) and Toll-like receptor 4 (TLR4) have been implicated in pro-inflammatory and prothrombotic histone responses. The objective of this study was to assess the role of vWF and TLR4 on histone-induced platelet adhesion in vivo.

Methods: Intravital microscopy of the mouse cremaster microcirculation, in the presence of extracellular histones or saline control, was conducted in wild-type, vWF-deficient, and TLR4-deficient mice to assess histone-mediated platelet adhesion. Platelet counts following extracellular histone exposure were conducted. Platelets were isolated from vWF-deficient mice and littermates to assess the role …

Development Of A Novel Mouse Model Of Menopause-Associated Asthma, William P Pederson, Laurie M Ellerman, Estevan C Sandoval, Scott Boitano, Jennifer B Frye, Kristian P Doyle, Heddwen L Brooks, Francesca Polverino, Julie G Ledford

Faculty, Staff and Students Publications

No abstract provided.

Clearance Of Hiv-1 Or Siv Reservoirs By Promotion Of Apoptosis And Inhibition Of Autophagy: Targeting Intracellular Molecules In Cure-Directed Strategies, Min Chen, Min Li, Marietta M Budai, Andrew P Rice, Jason T Kimata, Mahesh Mohan, Jin Wang

Faculty, Staff and Students Publications

The reservoirs of the HIV display cellular properties resembling long-lived immune memory cells that could be exploited for viral clearance. Our interest in developing a cure for HIV stems from the studies of immunologic memory against infections. We and others have found that long-lived immune memory cells employ prosurvival autophagy and antiapoptotic mechanisms to protect their longevity. Here, we describe the rationale for the development of an approach to clear HIV-1 by selective elimination of host cells harboring replication-competent HIV (SECH). While reactivation of HIV-1 in the host cells with latency reversing agents (LRAs) induces viral gene expression leading to …

Mitochondrial Dysfunction And Pharmacodynamics Of Mitofusin Activation In Murine Charcot-Marie-Tooth Disease Type 2a, Antonietta Franco, Xiawei Dang, Lihong Zhang, Perry B Molinoff, Gerald W Dorn 2nd

2020-Current year OA Pubs

Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity …

Altering Brain Amyloidosis By Intra-Lingual And Extra-Nasal Exposure Of Aβ Aggregates, Nazaret Gamez, Javiera Bravo-Alegria, Yumeng Huang, Nelson Perez-Urrutia, Deepa Dongarwar, Claudio Soto, Rodrigo Morales

Faculty, Staff and Student Publications

Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aβ seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aβ aggregates increased amyloid pathology in the olfactory bulb. Our …

Steroid Receptor Coactivator-3 Inhibition Generates Breast Cancer Antitumor Immune Microenvironment, Sang Jun Han, Nuri Sung, Jin Wang, Bert W O'Malley, David M Lonard

Faculty, Staff and Students Publications

BACKGROUND: The tumor immune microenvironment (TIME) generated by cancer-infiltrating immune cells has a crucial role in promoting or suppressing breast cancer progression. However, whether the steroid receptor coactivator-3 (SRC-3) modulates TIME to progress breast cancer is unclear. Therefore, the present study evaluates whether SRC-3 generates a tumor-promoting TIME in breast tumors using a syngeneic immune-intact mouse model of breast cancer.

METHODS: We employed E0771 and 4T1 breast cancer in immune-intact syngeneic female C57BL/6 and BALB/c mice, respectively. SI-2, a specific small-molecule inhibitor of SRC-3, was administered daily (2.5 mg/kg) to E0771 and 4T1 breast tumor-bearing immune-intact mice. In addition, SRC-3 …

Desmoglein-2 Is Important For Islet Function And Β-Cell Survival, Kay K. Myo Min, Darling Rojas-Canales, Daniella Penko, Mark Denichilo, Michaelia P. Cockshell, Charlie B. Ffrench, Emma J. Thompson, Olof Asplund, Christopher J. Drogemuller, Rashmi B. Prasad, Leif Groop, Shane T Grey, Helen E. Thomas, Thomas Loudovaris, Thomas W. Kay, My G. Mahoney, Claire F. Jessup, P. Toby Coates, Claudine S. Bonder

Department of Dermatology and Cutaneous Biology Faculty Papers

Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes …

Distinct Organization Of Two Cortico-Cortical Feedback Pathways, Shan Shen, Xiaolong Jiang, Federico Scala, Jiakun Fu, Paul Fahey, Dmitry Kobak, Zhenghuan Tan, Na Zhou, Jacob Reimer, Fabian Sinz, Andreas S Tolias

Duncan NRI Faculty and Staff Publications

Neocortical feedback is critical for attention, prediction, and learning. To mechanically understand its function requires deciphering its cell-type wiring. Recent studies revealed that feedback between primary motor to primary somatosensory areas in mice is disinhibitory, targeting vasoactive intestinal peptide-expressing interneurons, in addition to pyramidal cells. It is unknown whether this circuit motif represents a general cortico-cortical feedback organizing principle. Here we show that in contrast to this wiring rule, feedback between higher-order lateromedial visual area to primary visual cortex preferentially activates somatostatin-expressing interneurons. Functionally, both feedback circuits temporally sharpen feed-forward excitation eliciting a transient increase–followed by a prolonged decrease–in pyramidal …

Evaluation Of Allogeneic And Autologous Membrane-Bound Il-21-Expanded Nk Cells For Chronic Lymphocytic Leukemia Therapy, Max Yano, Chia Sharpe, J Rachel Lance, Janani Ravikrishnan, Kevan Zapolnik, Xiaokui Mo, Jennifer A Woyach, Deepa Sampath, Adam S Kittai, Sumithira Vasu, Seema Bhat, Kerry A Rogers, Dean A Lee, Natarajan Muthusamy, John C Byrd

Faculty, Staff and Student Publications

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with …

Ubr2 Targets Myosin Heavy Chain Iib And Iix For Degradation: Molecular Mechanism Essential For Cancer-Induced Muscle Wasting, Song Gao, Guohua Zhang, Zicheng Zhang, James Z Zhu, Li Li, Yong Zhou, George G Rodney, Reem S Abo-Zahrah, Lindsey Anderson, Jose M Garcia, Yong Tae Kwon, Yi-Ping Li

Faculty, Staff and Student Publications

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition …

Yap And Taz Promote Osteogenesis And Prevent Chondrogenesis In Neural Crest Cells In Vitro And In Vivo, Xiaolei Zhao, Li Tang, Tram P Le, Bao H Nguyen, Wen Chen, Mingjie Zheng, Hiroyuki Yamaguchi, Brian Dawson, Shuangjie You, Idaliz M Martinez-Traverso, Shannon Erhardt, Jianxin Wang, Min Li, James F Martin, Brendan H Lee, Yoshihiro Komatsu, Jun Wang

Faculty, Staff and Student Publications

Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute the majority of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in Yap and Taz switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for Yap and Taz resulted in bone loss and ectopic cartilage in mice. Yap bound to the regulatory elements of key …